Dopamine (DA) is a neurotransmitter that plays an essential role in normal brain functions. As a chemical messenger, dopamine is similar to adrenaline. In the brain, dopamine is synthesized in the pre-synaptic neurons and released into the space between the pre-synaptic and post-synaptic neurons.
Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain. Therefore, the regulation of dopamine plays an important role in mental and physical health. Neurons containing dopamine are clustered in the midbrain area called the substantia nigra. Abnormal dopamine signaling in the brain has been implicated in a substantial number of pathological conditions, including drug (e.g., cocaine) abuse, depression, anxiety, schizophrenia, Tourette's syndrome, eating disorders, alcoholism, chronic pain, obsessive compulsive disorders, restless leg syndrome, Parkinson's Disease, and the like.
Dopamine molecules bind to and activate dopamine receptors on the post-synaptic neurons. Dopamine molecules then are transported through the dopamine transporter protein (DAT) back into the pre-synaptic neurons, where they are metabolized by monoamine oxidase (MAO). In conditions such as cocaine abuse, cocaine binds to the dopamine transporter and blocks the normal flow of dopamine molecules. Excess concentrations of dopamine cause over-activation of dopamine receptors. In other conditions, such as Parkinson's Disease, lack of sufficient dopamine receptors in the brain causes insufficient activation of dopamine receptors.
Dopaminergic neurotransmission is mediated by five dopamine receptors (D1-D5) that can be grouped into the D1-like (D1 and D5) and D2-like (D2, D3 and D4) receptor subtypes. Recent studies suggest that the D3 receptor is a promising therapeutic target for a variety of conditions, including drug abuse, restless leg syndrome, schizophrenia, Parkinson's disease, and depression (1-6). Therefore, considerable effort has been expended to discover and develop potent and selective D3 ligands (6-22).
Despite these intense efforts, the design and discovery of truly selective D3 ligands with good aqueous solubility and bioavailability remains a challenge. Compound 1 (pramipexole) is a known, potent D3-preferring agonist, but has limited selectivity over the D2 receptor in vitro (23) and in vivo (24, 25). Compound 2 (BP 897) initially was reported as a D3 partial agonist and has a 67-fold selectivity over the D2 receptor (2).

A number of potent and selective D3 ligands, such as compound 3, have been designed based upon the core structure of compound 2 (17). Compound 4 is a potent and selective D3 ligand using hexahydropyrazinoquinoline as the core structure. Despite its relatively high affinity and excellent selectivity for D3 over other dopamine receptor subtypes, compound 4 has a poor aqueous solubility, which limits in vivo evaluations. Poor aqueous solubility also is a major limitation for many recently disclosed selective D3 ligands, and is an obstacle for evaluating these compounds in animal behavioral models and for a therapeutic potential.

Accordingly, a need still exists in the art for a potent and selective D3 ligand having physical and pharmacological properties that permit use of the ligand in therapeutic applications. The present invention provides ligands designed to selectively bind to the D3 receptor subtype to partially, or fully, modulate (e.g., agonism and/or antagonism) the D3 receptor with high selectivity.